Oxobutyrolactones



United States Patent 3,185,711 OXOBUTYROLACTONES Harold G. Monsimer, Philadelphia, Pa., assignor to Richardson-Merrell Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 19, 1963, Ser. No. 310,159 3 Claims. (Cl. 260-3435) This invention relates to substituted Z oxobutyrolactone derivatives. Specifically this invention relates to 4-substituted-3-carbethoxy 2 oxobutyrolactone derivatives which have useful antiviral activity.

The novel compounds described by the present invention are those corresponding to the formula:

C O 0 02115 O r. o

wherein R may be halogenor acylamino.

The compounds of this invention may be synthesized by reacting an appropriate aldehyde with the sodium salt of diethyloxal-acetate:

(lo-00 0 11 e) R- CHO Na I H-CO C H The reaction may be advantageously carried out at temperatures ranging from 20 to 100 C. for a period of four to forty-eight hours in a solvent medium such as methanol, ethanol, henzene, toluene, and the like.

The invention oxo-butyrolactones were found to exhibit useful antiviral activity and low toxicity when tested against the PR-8 strain of influenza virus by the twenty- =four hour mouse test (lung titrations), ten day survival test on infected mice (pre-- and post-treatment) and in vitro and in vivo (ovo) test in embryonated chicken eggs methods.

The following examples illustrate specific embodiments of the present invention.

EXAMPLE 1 3-carb ethoxy4-(p-acelam idophenyl -2-0xobutyrolact0ne resulted in the separation of a gum which was takenup in methylene chloride and washed with water. The solvent was removed and the residue crystallized from ethanol to give 3-carbethoxy-4-(pacetamidophenyl)-2-oxobutyrola-ctone melting at 177-179 C. AMZQYSiSr-CMOd. for C15H15NO6I C, 59.01; H, N, 4.59. Found: C, 58.76; H, 5.02; N, 4.33,

Procedure B.-A solution of 3-carbethoxy-4-(p-nitrophenyl)-2-oxobutyrolactone (30 grams, 0.1 mole) in 400 milliliters of ethanol containing 12 milliliters of concentrated hydrochloric acid was hydrogenated employing 1 gram of 10 percent palladium on charcoal as catalyst at room temperature and pounds of hydrogen pressure. After the theoretical amount of hydrogen was consumed,

the catalyst was removed by filtration, and 3-carbethoxy- 4-(p-aminophenyl) 2 oxobutyrolactone hydrochloride crystallized from the alcohol solution on standing,

3,185,711 Patented May 25, 1965 .4-(p-acetamidophenyl) 2 oxobutyrolactone melting at 171- 175 C. A mixture melting point with material obtained by procedure A was not depressed.

Preparation of 3-carbeth0xy-4-(p-nitrophenyl) -2- oxobutyrolactone A mixture of 15.8 grams (0.1 mole) of p-nitrobenzaldehyde and 19.7 grams (0.094 mole) of sodium diethyloxalacetate in milliliters of ethanol was stirred at room temperature for a period of twenty-four hours. The solvent was removed under reduced pressure and 100 milliliters of ether, 10 milliliters of concentrated hydrochloric acid, and 100 grams of ice were'added to the residue. After stirring for thirty minutes, the layers were separated and the aqueous layer extracted with two 100 milliliter portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give 3-carbethoxy-4-(p nitrophenyl)-2- oxobutyrolactone melting at -126 C.

Analysis.Calcd. for C H NO C, 53.24; H, 3.78; N, 4.78. Found: C, 52.90; H, 3.71; N, 4.66. 1

EXAMPLE 2 3 -carb eth 0xy-4 p-fluorophenyl -2-0x0butyr0lactone A mixture of p-fluorobenzaldehyde (12.5 grams, 0.1 mole) and sodium diethyl oxalacetate (21 grams, 0.1 mole) in 100 milliliters of ethanol was stirred for a period of thirty hours at room temperature. The solvent was removed under reduced pressure and 20 milliliters of concentrated hydrochloric acid was added with cooling, Two hundred milliliters of ether and 50 milliliters of water were added, and the solution was stirred until all solids were dissolved and the layers were separated. The ether layer was extracted with sodium bicarhonate solution which was then acidified to yield crude product, which was crystallized from ethanol to give 3- carbethoxy-4-(p-fiuorophenyl)-2-oxobutyrolactone having a melting point of 122.5-1235" C.

Analysis.Calcd. for C H O F: C, 58.62; H, 4.17. Found: C, 58198; H, 4.31.

What is claimed is: 1. A composition of the formula:

H- o I O R \O wherein R is a member selected from the group consisting of p-acetamidophenyl and p-fluorophenyl.

2. 3-carbethoxy-4-(p-acetamidophenyl) 2 oxobutyrolactone.

3. 3-carbethoxy-4-(p-fluorophenyl) 2 oxobutyrolau tone.

References Cited by the Examiner NICHOLAS S. RIZZO, Examiner.

Patent No. 3,185,711 May 25, 1965 Harold G. Monsimer It is hereby certified that error a ent requiring correction and that the sa corrected below.

ppears in the above numbered patid Letters Patent should read as Column 1, lines 14 to 19, the formula should appear as shown below instead of as in the patent:

CO C H Signed and sealed this 23rd day of November 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOSITION OF THE FORMULA: 